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PhD Defence Pedro GOMES

La soutenance de thèse le 18/12/2023 à 14h, à l’Ecole d’Ingénieurs de Purpan (75 Voie du Toec, 31076 Toulouse), amphi 65 (uniquement en présentiel).

Le projet est fruit d’un partenariat entre les équipes toulousaines BLADE (Toulouse Biotechnology Institute-INSA Toulouse), l’équipe NGN (ToxAlim-INRAE) et le groupe industriel lillois Lesaffre International. Il s’intitule : « Exploration du potentiel santé des souches de Lactococcus lactis productrices de GABA : vers de nouvelles stratégies thérapeutiques dans la gestion de l’hypersensibilité viscérale », présenté en langue française (abstract à la fin de ce message).

Le jury sera composé par :

  • Vincent JUILLARD (Rapporteur) : MICALYS-INRAE (Jouy-en-Josas)
  • Moïse COEFFIER (Rapporteur) : Université Rouen Normandie
  • Philippe LANGELLA (Examinateur) : MICALYS, INRAE (Jouy-en-Josas)
  • Muriel MERCIER-BONIN (Examinatrice) : TOXALIM-INRAE (Toulouse)
  • Sophie LEGRAIN-RASPAUD (Invitée): Gnosis by Lesaffre (Marcq-en-Baroeul)
  • Hélène EUTAMENE (Directrice de thèse) : TOXALIM-INRAE (Toulouse)
  • Muriel COCAIGN-BOUSQUET (Co-directrice de thèse) : TBI-INSA (Toulouse)

Abstract

   Irritable bowel syndrome (IBS) is a disabling chronic disease, recently classified under the new term “disorders of the gut-brain axis,” formerly known as “functional gastrointestinal disorders.” Clinically, according to the ROME IV criteria, IBS is characterized by heightened sensitivity and amplified pain perception in the gut, a phenomenon referred to as visceral hypersensitivity (VH), associated with bowel disturbances without identifiable organic causes. IBS symptoms have significant implications in terms of patient quality of life and costs, and they can trigger or exacerbate stress and anxiety. The pathophysiology of IBS remains poorly understood, and prescribed treatments are based on predominant symptoms and the severity of complaints. In this context, certain probiotic strains have the capacity to influence communication between the gut microbiota, the intestine, and the brain, thereby modulating visceral sensitivity through the release of specific neuromodulators produced by these bacteria. Among these modulators, γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter of the central nervous system that plays a key role in pain perception and relief in mammals. In several bacteria, an acid stress resistance system allows them to produce GABA after the decarboxylation of L-glutamic acid by the enzyme glutamate decarboxylase (GAD). This system is notably observed in lactic acid bacteria (LAB) like Lactococcus lactis (L. lactis), widely used in the food industry for its generally recognized as safe (GRAS) status. Although it has been observed that the commensal bacterium Bifidobacterium dentium is capable of reducing stress-induced VH in rats through GABA production, the ability of LAB to modulate visceral sensitivity via their capacity to produce GABA remains to be defined. Under identical culture conditions in a bioreactor, we characterized three strains of L. lactis with varying levels of GABA production (from low to high production) in relation to their GAD activity. We evaluated their abilities to reduce VH in response to acute stress in a rat model that mimics IBS symptoms. We qualified the L. lactis strain CNCM I-5388 as a hyperproducer of GABA compared to the reference strain NCDO2118 and we demonstrated that its antinociceptive properties become significant after only 5 days of oral treatment, compared to 10 days for NCDO2118. We also established that these properties, for both strains, are GAD/GABA-dependent, acting on the host’s GABAB receptors independently of changes in fecal microbiota alpha and beta diversities. Furthermore, we show that this effect does not depend on the cellular viability of L. lactis for strain CNCM I-5388. Indeed, in its postbiotic form (non-viable but with active GAD enzyme), we observe a similar effect to that of the strain in its probiotic form after 5 and 10 days of treatment. Finally, through analyses of rats’ gastrointestinal contents and static or dynamic models that mimic the human gastric compartment, our results suggest that a stomach-like pH might be the major player in bacterial GAD activation and GABA production to exert antinociceptive properties in vivo. Our conclusions indicate that GABA-producing L. lactis strains could be used therapeutically for the symptomatic treatment of disabling visceral pain in IBS and other pathologies.

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